3-49805382-C-G

Variant names:

• chr3-49805382-C-G
• rs781101993
• NM_003335.3:c.2965G>C

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003335.3(UBA7):​c.2965G>C​(p.Val989Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000929 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V989M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: UBA7 NM_003335.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34
• Publications: 0 publications found

Genes affected

UBA7 (HGNC:12471): (ubiquitin like modifier activating enzyme 7) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, or E1s, ubiquitin-conjugating enzymes, or E2s, and ubiquitin-protein ligases, or E3s. This gene encodes a member of the E1 ubiquitin-activating enzyme family. The encoded enzyme is a retinoid target that triggers promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARalpha) degradation and apoptosis in acute promyelocytic leukemia, where it is involved in the conjugation of the ubiquitin-like interferon-stimulated gene 15 protein. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.021273494).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003335.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA7	NM_003335.3	MANE Select	c.2965G>C	p.Val989Leu	missense	Exon 24 of 24	NP_003326.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UBA7	ENST00000333486.4	TSL:1 MANE Select	c.2965G>C	p.Val989Leu	missense	Exon 24 of 24	ENSP00000333266.3	P41226
	UBA7	ENST00000905619.1		c.2980G>C	p.Val994Leu	missense	Exon 24 of 24	ENSP00000575678.1
	UBA7	ENST00000905599.1		c.2965G>C	p.Val989Leu	missense	Exon 25 of 25	ENSP00000575658.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151920 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000169 AC: 42 AN: 248848 AF XY: 0.000267

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000999 AC: 146 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.000164 AC XY: 119 AN XY: 727216

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00168 AC: 145 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112002

Other (OTH) AF: 0.0000166 AC: 1 AN: 60394

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152038 Hom.: 0 Cov.: 30 AF XY: 0.0000538 AC XY: 4 AN XY: 74330

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

South Asian (SAS) AF: 0.000831 AC: 4 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67978

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.000165 AC: 20

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	14
DANN	Benign	0.53
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.3
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.13
Sift	Benign	0.61	T
Sift4G	Benign	0.64	T
Polyphen		0.0010	B
Vest4		0.27
MutPred		0.46		Loss of glycosylation at P985 (P = 0.0234)
MVP		0.25
MPC		0.23
ClinPred		0.23	T
GERP RS		4.5
Varity_R		0.068
gMVP		0.67
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781101993; hg19: chr3-49842815;